title: Stereochemistry-dependent inhibition of RAS farnesylation by farnesyl phosphonic acids.
abstract: This investigation compares the effects of three farnesyl pyrophosphate analogs on selected aspects of isoprenoid metabolism. E,E-alpha-Hydroxyfarnesylphosphonate was prepared by an improved variation on a literature synthesis, which also gave access to the new Z,E-alpha-hydroxyfarnesyl- and alpha-hydroxygeranylphosphonates. A striking find is that only E,E-alpha-hydroxyfarnesylphosphonate induces alteration of RAS processing in intact human-derived leukemia cells and inhibits farnesyl protein transferase in enzyme assays, while the Z,E-alpha-farnesyl- and geranylphosphonates are inactive. The inhibitory activity of E,E-alpha-hydroxyfarnesylphosphonate is greater in enzyme than intact cell assays. This active compound does not significantly inhibit geranylgeranyl protein transferase I or squalene synthase, nor does it diminish cholesterol synthesis. These results indicate that the length of the terpenoid chain and olefin stereochemistry allow selective inhibition of critical enzymes of terpenoid metabolism. Discrimination was observed between inhibition of farnesyl protein transferase and squalene synthase by E,E-alpha-hydroxyfarnesylphosphonate, even though both enzymes utilize farnesyl pyrophosphate as their natural substrate.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City 52242, USA. raymond-hohl@uiowa.edu
authors.forename: R J
authors.initials: RJ
authors.lastname: Hohl
authors.forename: K A
authors.initials: KA
authors.lastname: Lewis
authors.forename: D M
authors.initials: DM
authors.lastname: Cermak
authors.forename: D F
authors.initials: DF
authors.lastname: Wiemer
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005204:Farnesol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007938:Leukemia; D008968:Molecular Conformation; D063065:Organophosphonates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017368:Protein Prenylation / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C080570:(alpha-hydroxyfarnesyl)phosphonic acid; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D005204:Farnesol; D002784:Cholesterol; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D013186:Farnesyl-Diphosphate Farnesyltransferase; D018631:ras Proteins